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Biological ChemistryMolecular Biology

Introduction

We are working on the intersection of neuron and cancer. Post-mitotic neurons and indefinitely proliferating cancer cells look far from one another. However, there are many common molecules working in these different fields. We particularly focus on the tumorigenesis of neuroblastoma among cancer by approaching through genome, epigenome, proteome, and glycome. Regarding neuron, we are interested in microenvironment for axon injury and neurodegeneration. Investigation of roles of proteoglycans is a major theme.

Research Projects

1. Neuroblastoma research group

i) Background of neuroblastoma tumorigenesis

Neuroblastoma is the most common extracranial solid tumor of childhood. neuroblastoma mainly arises from adrenal grand or sympathetic ganglion. In general, the elder people have higher risk of tumors compared to younger ones, because the risk exposed to tumorigenic factors is accumulating during the lifetime. In contrast, the incidence of neuroblastoma, a pediatric tumor, is not related with ages, and the number of patients is much smaller than that of adult tumors. These facts implicate that the origin of neuroblastoma should be totally different from that of adult tumors.

 The origin cells of neuroblastoma are included in neural crest that appears at the early stage of embryogenesis. Neural crest contains several lineages of cell differentiating into melanocyte, enteric neuron, sensory neuron and so on. Among them, only the cells differentiating into sympathetic neuron have potential to proceed to neuroblastoma. This suggests that the mechanism by which neural crest cells differentiate into sympathetic neurons is indispensable for tumorigenesis of neuroblastoma, and that an abnormal events during that process should turn the tumorigenic switch on.

 So far, two predisposition genes of neuroblastoma, the transcription factor MYCN and receptor tyrosine kinase ALK, have been identified. MYCN has relatively longer history as a neuroblastoma-related gene, and its amplification observed in 20-30% of patients is the certain poor prognosis factor. On the other hand, it was recently reported that ALK was the predisposition gene of familial neuroblastoma, and several hyper-active point mutations were also identified in some sporadic neuroblastoma. The ectopic expression of MYCN during the differentiating process of sympathetic neuron should be the trigger of neuroblastoma tumorigenesis.

ii) An animal model for neuroblastoma and its significance

biochem01.jpgAs an animal model of neuroblastoma, MYCN transgenic mice (Th-MYCN mice), in which human MYCN gene was expressed under the control of tyrosine hydroxylase promoter (sympathetic neuron-specific), have been generated. These mice spontaneously develop neuroblastoma from superior mesenteric ganglion (SMG, one of the sympathetic ganglia) (upper pictures). As described above, the mechanism of neuroblastoma tumorigenesis should be totally different from that of adult tumors, and be based on the machinery of normal development. Because the machinery of embryonal development is highly conserved between human and mouse, Th-MYCN mice could accurately reproduce human neuroblastoma. Utilizing Th-MYCN mice, we are addressing the molecular mechanism of neuroblastoma.

iii) Tumorigenesis and spontaneous regression in Th-MYCN mice

 We are focusing on tumorigenesis and spontaneous regression in Th-MYCN mice. Spontaneous regression is the interesting phenomenon that the apparently terminal tumor with metastasis "spontaneously regresses" without any treatment. It is well known as stage 4S in neuroblastoma. Elucidating the mechanism of spontaneous regression could be useful to establish new therapeutic strategies. We found the spontaneous regression-like phenomenon in Th-MYCN mice (see "b" below). Th-MYCN mice must be beneficial in addressing the mechanism of not only tumorigenesis but also spontaneous regression of neuroblastoma.

  a) Tumorigenesis of neuroblastoma

biochem02.jpgWe sampled the SMG at early tumorigenic stage, and trying to identify the genes whose expression were changed compared to normal SMG through comprehensive gene expression analyses.

b) Spontaneous regression

So far, we cannot recognize the particular mouse that will undergo spontaneous regression afterward. On the other hand, we found that all 2-week old Th-MYCN mice showed precancerous symptom in their SMG, and that 70% among them developed neuroblastoma afterward. In other words, the precancerous neuroblasts in 30% of Th-MYCN mice disappeared. We suppose that this phenomenon might mimic the spontaneous regression of human neuroblastoma. We are trying to identify the genes whose expression levels vary among 2-week mice. Such genes could be involved in the regression.

The important concept related to both tumorigenesis and spontaneous regression is cancer stem cells. Tumorigenesis might be synonymous with the generation of cancer stem cells, and the presence or the strength of cancer stem cells might determine whether a tumor progresses or regresses. In order to selectively culture stem cells in vitro, researchers employ the sphere formation (right picture). We are searching the better condition to efficiently and selectively culture the tumor stem cells. Our purpose is the identification of cancer stem cell-specific profile in terms of gene expression. Such genes must be potent candidates for novel molecular therapy.

 

iv) Screening of new therapeutic targets based on synthetic lethality with MYCN amplification

MYCN gene amplification clearly correlates with poor prognosis in patients with neuroblastoma. Basically, transcriptional factors, including N-Myc, are thought to be “un-druggable” targets, and therefore, alternative strategies are required to develop new therapies. For instance, synthetic lethal (SL) approaches are emerging as a promising strategy for cancer therapy. SL genes are required for cell division in a cancer type-dependent manner. By identifying MYCN-amplified cell-specific SL genes, development of a safe and effective therapeutic approach would be possible. In order to find SL genes, we have performed a genome-wide shRNA library screening and identified new candidate genes. We are trying to develop new drugs for neuroblastoma treatment in collaboration with pharmaceutical companies.

2. Neuronal axon and glycan research group

 i) Research Background

The human neural circuit is about 50 thousand kilometers in length which is connected by axons. During development of the neuronal network, neurons connect with one another by extending their axons. The longest axon in human can stretch up to approximately 1 meter. 

The delicate neural circuit can be easily disrupted by physical forces. For example, spinal cord injury can cause a series of damage to the neuronal axons. Distal part of neurons undergo Wallerian degeneration and removed from tissue, while proximal part of neurons are still alive and try to extend their axons again to reconnect neural circuits. However, their efforts end up in vein. As a result, neural network permanently remains disconnected and patients suffer from paralysis for life. One of the reasons is the accumulation of chondroitin sulfate (CS) at the injury site. In contrast, heparan sulfate (HS) promotes axon growth. Interestingly, HS and CS are similar in molecular structure and bind to the same receptor, PTPRσ (a receptor type tyrosine protein phosphatase). However, it has been elusive why or how these similar glycans cause opposite effects on the axon regeneration through the same receptor. 

 ii) Research Achievement

Collaborating with Academia Sinica (Taiwan) and Tottori University (Japan), our research team chemically synthesized a series of HS and CS, which are different both in length and sulfation patterns. Our team found that HS could polymerize PTPRσ and promote axonal extension, while CS monomerized it and disrupted the extension. Upon binding to PTPRσ, CS activated this receptor’s enzymatic activity, and consequently dephosphorylated cortactin. As cortactin is critical for autophagy, CS-induced cortactin de-phosphorylation stopped autophagy and transformed axon tips to club-like structures, so-called dystrophic endballs, hallmark of injured axon. Indeed, an artificial disruption of autophagy induced dystrophic endballs (see Fig. Sakamoto, Ozaki, et al., Nat Chem Biol2019).

神経糖鎖HP 図.jpg

iii) Future Perspective

Importance of the current findings is that we have verified the mechanism of the inhibition of axon regeneration, namely the axis of CS-PTPRσ-cortactin-autophagy. The findings have provided important molecular targets to cure neuronal injuries. For example, HS oligosaccharides or PTPRσ inhibitors could be candidate therapeutics. In addition, since autophagy disruption is often observed in neurodegenerative diseases such as Parkinson’s disease and Alzheimer disease, our findings have provided insight into the mechanisms of these diseases.

Faculty Members

FacultyPositionDepartment
Kenji Kadomatsu Professor Molecular Biology
Shinichi Kiyonari Lecturer Molecular Biology
Kazuma Sakamoto Assistant Professor Molecular Biology
Tomoya Ozaki Assistant Professor Molecular Biology
Shoma Tsubota Assistant Professor Molecular Biology
Shaniya Abudureyimu Institutional researcher Molecular Biology

Bibliography

  • 2019
    1. Nariai Y, Kamino H, Obayashi E, Kato H, Sakashita G, Sugiura T, Migita K, Koga T, Kawakami A, Sakamoto K, Kadomatsu K, Nakakido M, Tsumoto K, Urano T. Generation and characterization of antagonistic anti-human interleukin (IL)-18 monoclonal antibodies with high affinity: Two types of monoclonal antibodies against full-length IL-18 and the neoepitope of inflammatory caspase-cleaved active IL-18. Arch. Biochem. Biophys. 2019 Jan 4;663:71-82.
    2. Takeda-Okuda N, Mizumoto S, Zhang Z, Kim SK, Lee CH, Jeon BT, Hosaka YZ, Kadomatsu K, Yamada S, Tamura JI. Compositional analysis of the glycosaminoglycan family in velvet antlers of Sika deer (Cervus nippon) at different growing stages. Glycoconj. J. 2019 Jan 24.
    3. Funahashi Y, Kato N, Masuda T, Nishio F, Kitai H, Ishimoto T, Kosugi T, Tsuboi N, Matsuda N, Maruyama S, Kadomatsu K. miR-146a targeted to splenic macrophages prevents sepsis-induced multiple organ injury. Lab. Invest. 2019 Jan 30.
    4. Narentuya, Takeda-Uchimura Y, Foyez T, Zhang Z, Akama TO, Yagi H, Kato K, Komatsu Y, Kadomatsu K, Uchimura K. GlcNAc6ST3 is a keratan sulfate sulfotransferase for the protein-tyrosine phosphatase PTPRZ in the adult brain. Sci Rep. 2019 Mar 13;9(1):4387.
    5. Sakamoto K, Ozaki,T, Yen-Chun Ko, Cheng-Fang Tsai, Gong Y, Morozumi,M, Ishikawa, Y, Uchimura K, Nadanaka S, Kitagawa H, Medel Manuel L. Zulueta, Anandaraju Bandaru, Tamura J, Shang-Cheng Hung, Kadomatsu K. Glycan sulfation patterns define autophagy flux at axon tip via PTPRσ-cortactin axis. Nature Chemical Biology, 2019.
  • 2018
    1. Doke T, Ishimoto T, Hayasaki T, Ikeda S, Hasebe M, Hirayama A, Soga T, Kato N, Kosugi T, Tsuboi N, Lanaspa MA, Johnson RJ, Kadomatsu K, Maruyama S. Lacking Ketohexokinase-A Exacerbates Renal Injury in Streptozotocin-induced Diabetic Mice. Metabolism, 2018.
    2. Tsubota S, Kadomatsu K. Origin and initiation mechanisms of neuroblastoma. Cell Tissue Res, 2018; 372: 211-221.
    3. Mori Y, Masuda T, Kosugi T, Yoshioka T, Hori M, Nagaya H, Maeda K, Sato Y, Kojima H, Kato N, Ishimoto T, Katsuno T, Yuzawa Y, Kadomatsu K, Maruyama S. The clinical relevance of plasma CD147/basigin in biopsy-proven kidney diseases. Clin Exp Nephrol, 2018; 22: 815-824.
  • 2017
    1. Su Z, Kishida S, Tsubota S, Sakamoto K, Cao D, Kiyonari S, Ohira M, Kamijo T, Narita A, Xu Y, Takahashi Y, Kadomatsu K. Neurocan, an extracellular chondroitin sulfate proteoglycan, stimulates neuroblastoma cells to promote malignant phenotypes. Oncotarget, 2017; 8: 106296-106310.
    2. Tsubota S, Kadomatsu K. Origin and mechanism of neuroblastoma. Oncoscience, 2017; 4: 70-72.
    3. Aynacioglu AS, Bilir A, Kadomatsu K. Dual inhibition of P-glycoprotein and midkine may increase therapeutic effects of anticancer drugs. Med Hypotheses, 2017; 107: 26-28.
    4. Misa K, Tanino Y, Wang X, Nikaido T, Kikuchi M, Sato Y, Togawa R, Tanino M, Tanaka S, Kadomatsu K, Munakata M. Involvement of midkine in the development of pulmonary fibrosis. Physiol Rep, 2017; 5.
    5. Tsubota S, Kishida S, Shimamura T, Ohira M, Yamashita S, Cao D, Kiyonari S, Ushijima T, Kadomatsu K. PRC2-Mediated Transcriptomic Alterations at the Embryonic Stage Govern Tumorigenesis and Clinical Outcome in MYCN-Driven Neuroblastoma. Cancer Res, 2017; 77: 5259-5271.
    6. Takemoto Y, Horiba M, Harada M, Sakamoto K, Takeshita K, Murohara T, Kadomatsu K, Kamiya K. Midkine Promotes Atherosclerotic Plaque Formation Through Its Pro-Inflammatory, Angiogenic and Anti-Apoptotic Functions in Apolipoprotein E-Knockout Mice. Circ J, 2017; 82: 19-27.
    7. Ichihara-Tanaka K, Kadomatsu K, Kishida S. Temporally and Spatially Regulated Expression of the Linker Histone H1fx During Mouse Development. J Histochem Cytochem, 2017; 65: 513-530.
    8. Ohgomori T, Yamasaki R, Takeuchi H, Kadomatsu K, Kira JI, Jinno S. Differential activation of neuronal and glial STAT3 in the spinal cord of the SOD1G93A mouse model of amyotrophic lateral sclerosis. Eur J Neurosci, 2017; 46: 2001-2014.
    9. Tsubota S, Kadomatsu K. Neuroblastoma stem cells and CFC1. Oncotarget, 2017; 8: 45032-45033.
    10. Mu P, Akashi T, Lu F, Kishida S, Kadomatsu K. A novel nuclear complex of DRR1, F-actin and COMMD1 involved in NF-kappaB degradation and cell growth suppression in neuroblastoma. Oncogene, 2017; 36: 5745-5756.
    11. Sakamoto K, Kadomatsu K. Mechanisms of axon regeneration: The significance of proteoglycans. Biochim Biophys Acta, 2017; 1861: 2435-2441.
    12. Ohgomori T, Yamasaki R, Takeuchi H, Kadomatsu K, Kira JI, Jinno S. Differential involvement of vesicular and glial glutamate transporters around spinal alpha-motoneurons in the pathogenesis of SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Neuroscience, 2017; 356: 114-124.
    13. Jiang W, Ishino Y, Hashimoto H, Keino-Masu K, Masu M, Uchimura K, Kadomatsu K, Yoshimura T, Ikenaka K. Sulfatase 2 Modulates Fate Change from Motor Neurons to Oligodendrocyte Precursor Cells through Coordinated Regulation of Shh Signaling with Sulfatase 1. Dev Neurosci, 2017; 39: 361-374.
    14. Matsumoto N, Konno A, Ohbayashi Y, Inoue T, Matsumoto A, Uchimura K, Kadomatsu K, Okazaki S. Correction of spherical aberration in multi-focal multiphoton microscopy with spatial light modulator. Opt Express, 2017; 25: 7055-7068.
    15. Zhang Z, Takeda-Uchimura Y, Foyez T, Ohtake-Niimi S, Narentuya, Akatsu H, Nishitsuji K, Michikawa M, Wyss-Coray T, Kadomatsu K, Uchimura K. Deficiency of a sulfotransferase for sialic acid-modified glycans mitigates Alzheimer's pathology. Proc Natl Acad Sci U S A, 2017; 114: E2947-E2954.
    16. Yoshimura T, Hayashi A, Handa-Narumi M, Yagi H, Ohno N, Koike T, Yamaguchi Y, Uchimura K, Kadomatsu K, Sedzik J, Kitamura K, Kato K, Trapp BD, Baba H, Ikenaka K. GlcNAc6ST-1 regulates sulfation of N-glycans and myelination in the peripheral nervous system. Sci Rep, 2017; 7: 42257.
    17. Masuda T, Maeda K, Sato W, Kosugi T, Sato Y, Kojima H, Kato N, Ishimoto T, Tsuboi N, Uchimura K, Yuzawa Y, Maruyama S, Kadomatsu K. Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis. Am J Pathol, 2017; 187: 740-751.
    18. Hayashi H, Sato W, Kosugi T, Nishimura K, Sugiyama D, Asano N, Ikematsu S, Komori K, Nishiwaki K, Kadomatsu K, Matsuo S, Maruyama S, Yuzawa Y. Efficacy of urinary midkine as a biomarker in patients with acute kidney injury. Clin Exp Nephrol, 2017; 21: 597-607.
    19. Scilabra SD, Yamamoto K, Pigoni M, Sakamoto K, Muller SA, Papadopoulou A, Lichtenthaler SF, Troeberg L, Nagase H, Kadomatsu K. Dissecting the interaction between tissue inhibitor of metalloproteinases-3 (TIMP-3) and low density lipoprotein receptor-related protein-1 (LRP-1): Development of a \"TRAP\" to increase levels of TIMP-3 in the tissue. Matrix Biol, 2017; 59: 69-79.
  • 2016
    1. Ho WL, Hsu WM, Huang MC, Kadomatsu K, Nakagawara A. Protein glycosylation in cancers and its potential therapeutic applications in neuroblastoma. J Hematol Oncol, 2016; 9: 100.
    2. Ukai J, Imagama S, Ohgomori T, Ito Z, Ando K, Ishiguro N, Kadomatsu K. Nogo receptor 1 is expressed in both primary cultured glial cells and neurons. Nagoya J Med Sci, 2016; 78: 303-311.
    3. Zhang Z, Ohtake-Niimi S, Kadomatsu K, Uchimura K. Reduced molecular size and altered disaccharide composition of cerebral chondroitin sulfate upon Alzheimer's pathogenesis in mice. Nagoya J Med Sci, 2016; 78: 293-301.
    4. Murakami-Tonami Y, Ikeda H, Yamagishi R, Inayoshi M, Inagaki S, Kishida S, Komata Y, Jan K, Takeuchi I, Kondo Y, Maeda T, Sekido Y, Murakami H, Kadomatsu K. SGO1 is involved in the DNA damage response in MYCN-amplified neuroblastoma cells. Sci Rep, 2016; 6: 31615.
    5. Hayashi H, Sato W, Kosugi T, Nishimura K, Sugiyama D, Asano N, Ikematsu S, Komori K, Nishiwaki K, Kadomatsu K, Matsuo S, Maruyama S, Yuzawa Y. Efficacy of urinary midkine as a biomarker in patients with acute kidney injury. Clin Exp Nephrol, 2016.
    6. Honda Y, Shishido T, Takahashi T, Watanabe T, Netsu S, Kinoshita D, Narumi T, Kadowaki S, Nishiyama S, Takahashi H, Arimoto T, Miyamoto T, Kishida S, Kadomatsu K, Takeishi Y, Kubota I. Midkine Deteriorates Cardiac Remodeling via Epidermal Growth Factor Receptor Signaling in Chronic Kidney Disease. Hypertension, 2016; 67: 857-865.
    7. Ohgomori T, Yamada J, Takeuchi H, Kadomatsu K, Jinno S. Comparative morphometric analysis of microglia in the spinal cord of SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis. Eur J Neurosci, 2016; 43: 1340-1351.
    8. Suzuki K, Satoh K, Ikeda S, Sunamura S, Otsuki T, Satoh T, Kikuchi N, Omura J, Kurosawa R, Nogi M, Numano K, Sugimura K, Aoki T, Tatebe S, Miyata S, Mukherjee R, Spinale FG, Kadomatsu K, Shimokawa H. Basigin Promotes Cardiac Fibrosis and Failure in Response to Chronic Pressure Overload in Mice. Arterioscler Thromb Vasc Biol, 2016; 36: 636-646.
    9. Hashimoto H, Ishino Y, Jiang W, Yoshimura T, Takeda-Uchimura Y, Uchimura K, Kadomatsu K, Ikenaka K. Keratan Sulfate Regulates the Switch from Motor Neuron to Oligodendrocyte Generation During Development of the Mouse Spinal Cord. Neurochem Res, 2016; 41: 450-462.
  • 2015
    1. Kamiguchi H, Kadomatsu K. Introduction to glyco-neuroscience. Exp Neurol, 2015; 274: 89.
    2. Fujimoto H, Ohgomori T, Abe K, Uchimura K, Kadomatsu K, Jinno S. Time-dependent localization of high- and low-sulfated keratan sulfates in the song nuclei of developing zebra finches. Eur J Neurosci, 2015; 42: 2716-2725.
    3. Foyez T, Takeda-Uchimura Y, Ishigaki S, Narentuya, Zhang Z, Sobue G, Kadomatsu K, Uchimura K. Microglial keratan sulfate epitope elicits in central nervous tissues of transgenic model mice and patients with amyotrophic lateral sclerosis. Am J Pathol, 2015; 185: 3053-3065.
    4. Ueno R, Miyamoto K, Tanaka N, Moriguchi K, Kadomatsu K, Kusunoki S. Keratan sulfate exacerbates experimental autoimmune encephalomyelitis. J Neurosci Res, 2015; 93: 1874-1880.
    5. Takeda-Uchimura Y, Uchimura K, Sugimura T, Yanagawa Y, Kawasaki T, Komatsu Y, Kadomatsu K. Requirement of keratan sulfate proteoglycan phosphacan with a specific sulfation pattern for critical period plasticity in the visual cortex. Exp Neurol, 2015; 274: 145-155.
    6. Kiyonari S, Iimori M, Matsuoka K, Watanabe S, Morikawa-Ichinose T, Miura D, Niimi S, Saeki H, Tokunaga E, Oki E, Morita M, Kadomatsu K, Maehara Y, Kitao H. The 1,2-Diaminocyclohexane Carrier Ligand in Oxaliplatin Induces p53-Dependent Transcriptional Repression of Factors Involved in Thymidylate Biosynthesis. Mol Cancer Ther, 2015; 14: 2332-2342.
    7. Maeda K, Kosugi T, Sato W, Kojima H, Sato Y, Kamimura D, Kato N, Tsuboi N, Yuzawa Y, Matsuo S, Murakami M, Maruyama S, Kadomatsu K. CD147/basigin limits lupus nephritis and Th17 cell differentiation in mice by inhibiting the interleukin-6/STAT-3 pathway. Arthritis Rheumatol, 2015; 67: 2185-2195.
    8. Matsuda Y, Haneda M, Kadomatsu K, Kobayashi T. A proliferation-inducing ligand sustains the proliferation of human naive (CD27(-)) B cells and mediates their differentiation into long-lived plasma cells in vitro via transmembrane activator and calcium modulator and cyclophilin ligand interactor and B-cell mature antigen. Cell Immunol, 2015; 295: 127-136.
    9. Arima H, Omura T, Hayasaka T, Masaki N, Hanada M, Xu D, Banno T, Kobayashi K, Takeuchi H, Kadomatsu K, Matsuyama Y, Setou M. Reductions of docosahexaenoic acid-containing phosphatidylcholine levels in the anterior horn of an ALS mouse model. Neuroscience, 2015; 297: 127-136.
    10. Chen D, Ito S, Yuan H, Hyodo T, Kadomatsu K, Hamaguchi M, Senga T. EML4 promotes the loading of NUDC to the spindle for mitotic progression. Cell Cycle, 2015; 14: 1529-1539.
    11. Ishikawa Y, Imagama S, Ohgomori T, Ishiguro N, Kadomatsu K. A combination of keratan sulfate digestion and rehabilitation promotes anatomical plasticity after rat spinal cord injury. Neurosci Lett, 2015; 593: 13-18.
    12. Yuan Y, Makita N, Cao D, Mihara K, Kadomatsu K, Takei Y. Atelocollagen-mediated intravenous siRNA delivery specific to tumor tissues orthotopically xenografted in prostates of nude mice and its anticancer effects. Nucleic Acid Ther, 2015; 25: 85-94.
    13. Lu F, Kishida S, Mu P, Huang P, Cao D, Tsubota S, Kadomatsu K. NeuroD1 promotes neuroblastoma cell growth by inducing the expression of ALK. Cancer Sci, 2015; 106: 390-396.
    14. Nakaguro M, Kiyonari S, Kishida S, Cao D, Murakami-Tonami Y, Ichikawa H, Takeuchi I, Nakamura S, Kadomatsu K. Nucleolar protein PES1 is a marker of neuroblastoma outcome and is associated with neuroblastoma differentiation. Cancer Sci, 2015; 106: 237-243.
    15. Sato Y, Sato W, Maruyama S, Wilcox CS, Falck JR, Masuda T, Kosugi T, Kojima H, Maeda K, Furuhashi K, Ando M, Imai E, Matsuo S, Kadomatsu K. Midkine Regulates BP through Cytochrome P450-Derived Eicosanoids. J Am Soc Nephrol, 2015; 26: 1806-1815.
    16. Kiyonari S, Kadomatsu K. Neuroblastoma models for insights into tumorigenesis and new therapies. Expert Opin Drug Discov, 2015; 10: 53-62.
    17. Kosugi T, Maeda K, Sato W, Maruyama S, Kadomatsu K. CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint. Nephrol Dial Transplant, 2015; 30: 1097-1103.
  • 2014
    1. Satoh K, Satoh T, Kikuchi N, Omura J, Kurosawa R, Suzuki K, Sugimura K, Aoki T, Nochioka K, Tatebe S, Miyamichi-Yamamoto S, Miura M, Shimizu T, Ikeda S, Yaoita N, Fukumoto Y, Minami T, Miyata S, Nakamura K, Ito H, Kadomatsu K, Shimokawa H. Basigin mediates pulmonary hypertension by promoting inflammation and vascular smooth muscle cell proliferation. Circ Res, 2014; 115: 738-750.
    2. Shinjo R, Imagama S, Ito Z, Ando K, Nishida Y, Ishiguro N, Kadomatsu K. Keratan sulfate expression is associated with activation of a subpopulation of microglia/macrophages in Wallerian degeneration. Neurosci Lett, 2014; 579: 80-85.
    3. Moreno V, Gonzalo P, Gomez-Escudero J, Pollan A, Acin-Perez R, Breckenridge M, Yanez-Mo M, Barreiro O, Orsenigo F, Kadomatsu K, Chen CS, Enriquez JA, Dejana E, Sanchez-Madrid F, Arroyo AG. An EMMPRIN-gamma-catenin-Nm23 complex drives ATP production and actomyosin contractility at endothelial junctions. J Cell Sci, 2014; 127: 3768-3781.
    4. Kadomatsu K, Sakamoto K. Mechanisms of axon regeneration and its inhibition: roles of sulfated glycans. Arch Biochem Biophys, 2014; 558: 36-41.
    5. Miyamoto K, Tanaka N, Moriguchi K, Ueno R, Kadomatsu K, Kitagawa H, Kusunoki S. Chondroitin 6-O-sulfate ameliorates experimental autoimmune encephalomyelitis. Glycobiology, 2014; 24: 469-475.
    6. Murakami-Tonami Y, Kishida S, Takeuchi I, Katou Y, Maris JM, Ichikawa H, Kondo Y, Sekido Y, Shirahige K, Murakami H, Kadomatsu K. Inactivation of SMC2 shows a synergistic lethal response in MYCN-amplified neuroblastoma cells. Cell Cycle, 2014; 13: 1115-1131.
    7. Maeda-Hori M, Kosugi T, Kojima H, Sato W, Inaba S, Maeda K, Nagaya H, Sato Y, Ishimoto T, Ozaki T, Tsuboi N, Muro Y, Yuzawa Y, Imai E, Johnson RJ, Matsuo S, Kadomatsu K, Maruyama S. Plasma CD147 reflects histological features in patients with lupus nephritis. Lupus, 2014; 23: 342-352.
    8. Cao D, Kishida S, Huang P, Mu P, Tsubota S, Mizuno M, Kadomatsu K. A new tumorsphere culture condition restores potentials of self-renewal and metastasis of primary neuroblastoma in a mouse neuroblastoma model. PLoS One, 2014; 9: e86813.
    9. Muramatsu T, Kadomatsu K. Midkine: an emerging target of drug development for treatment of multiple diseases. Br J Pharmacol, 2014; 171: 811-813.
    10. Nagaya H, Kosugi T, Maeda-Hori M, Maeda K, Sato Y, Kojima H, Hayashi H, Kato N, Ishimoto T, Sato W, Yuzawa Y, Matsuo S, Kadomatsu K, Maruyama S. CD147/basigin reflects renal dysfunction in patients with acute kidney injury. Clin Exp Nephrol, 2014; 18: 746-754.
    11. Kadomatsu K, Bencsik P, Gorbe A, Csonka C, Sakamoto K, Kishida S, Ferdinandy P. Therapeutic potential of midkine in cardiovascular disease. Br J Pharmacol, 2014; 171: 936-944.
    12. Kadomatsu K, Sakamoto K. Sulfated glycans in network rewiring and plasticity after neuronal injuries. Neurosci Res, 2014; 78: 50-54.
    13. Hoshino H, Foyez T, Ohtake-Niimi S, Takeda-Uchimura Y, Michikawa M, Kadomatsu K, Uchimura K. KSGal6ST is essential for the 6-sulfation of galactose within keratan sulfate in early postnatal brain. J Histochem Cytochem, 2014; 62: 145-156.
    14. Kishida S, Kadomatsu K. Involvement of midkine in neuroblastoma tumourigenesis. Br J Pharmacol, 2014; 171: 896-904.
  • 2013
    1. Hasan MK, Nafady A, Takatori A, Kishida S, Ohira M, Suenaga Y, Hossain S, Akter J, Ogura A, Nakamura Y, Kadomatsu K, Nakagawara A. ALK is a MYCN target gene and regulates cell migration and invasion in neuroblastoma. Sci Rep, 2013; 3: 3450.
    2. Matsui H, Ohgomori T, Natori T, Miyamoto K, Kusunoki S, Sakamoto K, Ishiguro N, Imagama S, Kadomatsu K. Keratan sulfate expression in microglia is diminished in the spinal cord in experimental autoimmune neuritis. Cell Death Dis, 2013; 4: e946.
    3. Duverle DA, Takeuchi I, Murakami-Tonami Y, Kadomatsu K, Tsuda K. Discovering combinatorial interactions in survival data. Bioinformatics, 2013; 29: 3053-3059.
    4. Hirano K, Ohgomori T, Kobayashi K, Tanaka F, Matsumoto T, Natori T, Matsuyama Y, Uchimura K, Sakamoto K, Takeuchi H, Hirakawa A, Suzumura A, Sobue G, Ishiguro N, Imagama S, Kadomatsu K. Ablation of keratan sulfate accelerates early phase pathogenesis of ALS. PLoS One, 2013; 8: e66969.
    5. Muramoto A, Imagama S, Natori T, Wakao N, Ando K, Tauchi R, Hirano K, Shinjo R, Matsumoto T, Ishiguro N, Kadomatsu K. Midkine overcomes neurite outgrowth inhibition of chondroitin sulfate proteoglycan without glial activation and promotes functional recovery after spinal cord injury. Neurosci Lett, 2013; 550: 150-155.
    6. Kadomatsu K, Kishida S, Tsubota S. The heparin-binding growth factor midkine: the biological activities and candidate receptors. J Biochem, 2013; 153: 511-521.
    7. Kobayashi K, Imagama S, Ohgomori T, Hirano K, Uchimura K, Sakamoto K, Hirakawa A, Takeuchi H, Suzumura A, Ishiguro N, Kadomatsu K. Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis, 2013; 4: e525.
    8. Kishida S, Mu P, Miyakawa S, Fujiwara M, Abe T, Sakamoto K, Onishi A, Nakamura Y, Kadomatsu K. Midkine promotes neuroblastoma through Notch2 signaling. Cancer Res, 2013; 73: 1318-1327.
    9. Kojima H, Kosugi T, Sato W, Sato Y, Maeda K, Kato N, Kato K, Inaba S, Ishimoto T, Tsuboi N, Matsuo S, Maruyama S, Yuzawa Y, Kadomatsu K. Deficiency of growth factor midkine exacerbates necrotizing glomerular injuries in progressive glomerulonephritis. Am J Pathol, 2013; 182: 410-419.
  • 2012
    1. Sakamoto K, Kadomatsu K. Midkine in the pathology of cancer, neural disease, and inflammation. Pathol Int, 2012; 62: 445-455.
    2. Matsumoto T, Imagama S, Hirano K, Ohgomori T, Natori T, Kobayashi K, Muramoto A, Ishiguro N, Kadomatsu K. CD44 expression in astrocytes and microglia is associated with ALS progression in a mouse model. Neurosci Lett, 2012; 520: 115-120.
    3. Koide N, Yasuda K, Kadomatsu K, Takei Y. Establishment and optimal culture conditions of microrna-induced pluripotent stem cells generated from HEK293 cells via transfection of microrna-302s expression vector. Nagoya J Med Sci, 2012; 74: 157-165.
    4. Tauchi R, Imagama S, Ohgomori T, Natori T, Shinjo R, Ishiguro N, Kadomatsu K. ADAMTS-13 is produced by glial cells and upregulated after spinal cord injury. Neurosci Lett, 2012; 517: 1-6.
    5. Tauchi R, Imagama S, Natori T, Ohgomori T, Muramoto A, Shinjo R, Matsuyama Y, Ishiguro N, Kadomatsu K. The endogenous proteoglycan-degrading enzyme ADAMTS-4 promotes functional recovery after spinal cord injury. J Neuroinflammation, 2012; 9: 53.
    6. Sonobe Y, Li H, Jin S, Kishida S, Kadomatsu K, Takeuchi H, Mizuno T, Suzumura A. Midkine inhibits inducible regulatory T cell differentiation by suppressing the development of tolerogenic dendritic cells. J Immunol, 2012; 188: 2602-2611.
    7. Sakai K, Yamamoto A, Matsubara K, Nakamura S, Naruse M, Yamagata M, Sakamoto K, Tauchi R, Wakao N, Imagama S, Hibi H, Kadomatsu K, Ishiguro N, Ueda M. Human dental pulp-derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro-regenerative mechanisms. J Clin Invest, 2012; 122: 80-90.
    8. Inaba S, Nagahara S, Makita N, Tarumi Y, Ishimoto T, Matsuo S, Kadomatsu K, Takei Y. Atelocollagen-mediated systemic delivery prevents immunostimulatory adverse effects of siRNA in mammals. Mol Ther, 2012; 20: 356-366.
  • 2011
    1. Imagama S, Sakamoto K, Tauchi R, Shinjo R, Ohgomori T, Ito Z, Zhang H, Nishida Y, Asami N, Takeshita S, Sugiura N, Watanabe H, Yamashita T, Ishiguro N, Matsuyama Y, Kadomatsu K. Keratan sulfate restricts neural plasticity after spinal cord injury. J Neurosci, 2011; 31: 17091-17102.
    2. Huet E, Vallee B, Delbe J, Mourah S, Pruliere-Escabasse V, Tremouilleres M, Kadomatsu K, Doan S, Baudouin C, Menashi S, Gabison EE. EMMPRIN modulates epithelial barrier function through a MMP-mediated occludin cleavage: implications in dry eye disease. Am J Pathol, 2011; 179: 1278-1286.
    3. Ishiguro H, Horiba M, Takenaka H, Sumida A, Opthof T, Ishiguro YS, Kadomatsu K, Murohara T, Kodama I. A single intracoronary injection of midkine reduces ischemia/reperfusion injury in Swine hearts: a novel therapeutic approach for acute coronary syndrome. Front Physiol, 2011; 2: 27.
    4. Hayashi M, Kadomatsu K, Kojima T, Ishiguro N. Keratan sulfate and related murine glycosylation can suppress murine cartilage damage in vitro and in vivo. Biochem Biophys Res Commun, 2011; 409: 732-737.
    5. Kadomatsu K. [Proteoglycans and neural circuit reconstruction]. Seikagaku, 2011; 83: 240-246.
    6. Kato K, Kosugi T, Sato W, Arata-Kawai H, Ozaki T, Tsuboi N, Ito I, Tawada H, Yuzawa Y, Matsuo S, Kadomatsu K, Maruyama S. Growth factor Midkine is involved in the pathogenesis of renal injury induced by protein overload containing endotoxin. Clin Exp Nephrol, 2011; 15: 346-354.
    7. Huang P, Kishida S, Cao D, Murakami-Tonami Y, Mu P, Nakaguro M, Koide N, Takeuchi I, Onishi A, Kadomatsu K. The neuronal differentiation factor NeuroD1 downregulates the neuronal repellent factor Slit2 expression and promotes cell motility and tumor formation of neuroblastoma. Cancer Res, 2011; 71: 2938-2948.
    8. Kato N, Kosugi T, Sato W, Ishimoto T, Kojima H, Sato Y, Sakamoto K, Maruyama S, Yuzawa Y, Matsuo S, Kadomatsu K. Basigin/CD147 promotes renal fibrosis after unilateral ureteral obstruction. Am J Pathol, 2011; 178: 572-579.
    9. Sakamoto K, Bu G, Chen S, Takei Y, Hibi K, Kodera Y, McCormick LM, Nakao A, Noda M, Muramatsu T, Kadomatsu K. Premature ligand-receptor interaction during biosynthesis limits the production of growth factor midkine and its receptor LDL receptor-related protein 1. J Biol Chem, 2011; 286: 8405-8413.
    10. Wakao N, Imagama S, Zhang H, Tauchi R, Muramoto A, Natori T, Takeshita S, Ishiguro N, Matsuyama Y, Kadomatsu K. Hyaluronan oligosaccharides promote functional recovery after spinal cord injury in rats. Neurosci Lett, 2011; 488: 299-304.
  • 2010
    1. Hayashi M, Kadomatsu K, Ishiguro N. Keratan sulfate suppresses cartilage damage and ameliorates inflammation in an experimental mice arthritis model. Biochem Biophys Res Commun, 2010; 401: 463-468.
    2. Ito Z, Sakamoto K, Imagama S, Matsuyama Y, Zhang H, Hirano K, Ando K, Yamashita T, Ishiguro N, Kadomatsu K. N-acetylglucosamine 6-O-sulfotransferase-1-deficient mice show better functional recovery after spinal cord injury. J Neurosci, 2010; 30: 5937-5947.
    3. Kadomatsu K. Midkine regulation of the renin-angiotensin system. Curr Hypertens Rep, 2010; 12: 74-79.
    4. Asano Y, Kishida S, Mu P, Sakamoto K, Murohara T, Kadomatsu K. DRR1 is expressed in the developing nervous system and downregulated during neuroblastoma carcinogenesis. Biochem Biophys Res Commun, 2010; 394: 829-835.
    5. Miwa Y, Yamamoto K, Onishi A, Iwamoto M, Yazaki S, Haneda M, Iwasaki K, Liu D, Ogawa H, Nagasaka T, Uchida K, Nakao A, Kadomatsu K, Kobayashi T. Potential value of human thrombomodulin and DAF expression for coagulation control in pig-to-human xenotransplantation. Xenotransplantation, 2010; 17: 26-37.
    6. Sumida A, Horiba M, Ishiguro H, Takenaka H, Ueda N, Ooboshi H, Opthof T, Kadomatsu K, Kodama I. Midkine gene transfer after myocardial infarction in rats prevents remodelling and ameliorates cardiac dysfunction. Cardiovasc Res, 2010; 86: 113-121.
  • 2009
    1. Hobo A, Yuzawa Y, Kosugi T, Kato N, Asai N, Sato W, Maruyama S, Ito Y, Kobori H, Ikematsu S, Nishiyama A, Matsuo S, Kadomatsu K. The growth factor midkine regulates the renin-angiotensin system in mice. J Clin Invest, 2009; 119: 1616-1625.
    2. Kato N, Yuzawa Y, Kosugi T, Hobo A, Sato W, Miwa Y, Sakamoto K, Matsuo S, Kadomatsu K. The E-selectin ligand basigin/CD147 is responsible for neutrophil recruitment in renal ischemia/reperfusion. J Am Soc Nephrol, 2009; 20: 1565-1576.
    3. Sakakima H, Yoshida Y, Yamazaki Y, Matsuda F, Ikutomo M, Ijiri K, Muramatsu H, Muramatsu T, Kadomatsu K. Disruption of the midkine gene (Mdk) delays degeneration and regeneration in injured peripheral nerve. J Neurosci Res, 2009; 87: 2908-2915.
    4. Mu P, Nagahara S, Makita N, Tarumi Y, Kadomatsu K, Takei Y. Systemic delivery of siRNA specific to tumor mediated by atelocollagen: combined therapy using siRNA targeting Bcl-xL and cisplatin against prostate cancer. Int J Cancer, 2009; 125: 2978-2990.
    5. Yin J, Sakamoto K, Zhang H, Ito Z, Imagama S, Kishida S, Natori T, Sawada M, Matsuyama Y, Kadomatsu K. Transforming growth factor-beta1 upregulates keratan sulfate and chondroitin sulfate biosynthesis in microglias after brain injury. Brain Res, 2009; 1263: 10-22.
    6. Takenaka H, Horiba M, Ishiguro H, Sumida A, Hojo M, Usui A, Akita T, Sakuma S, Ueda Y, Kodama I, Kadomatsu K. Midkine prevents ventricular remodeling and improves long-term survival after myocardial infarction. Am J Physiol Heart Circ Physiol, 2009; 296: H462-469.
    7. Kobayashi T, Liu D, Ogawa H, Miwa Y, Nagasaka T, Maruyama S, Li YT, Onishi A, Iwamoto M, Kuzuya T, Kadomatsu K, Uchida K, Nakao A. Removal of blood group A/B antigen in organs by ex vivo and in vivo administration of endo-beta-galactosidase (ABase) for ABO-incompatible transplantation. Transpl Immunol, 2009; 20: 132-138.

Research Keywords

Neuroblastoma、 MYCN transgenic mice、 Tumor-Initiating cells、 spontaneous regression、proteoglycans、 keratan sulfate、 central nervous system、 plasticity

Call for Graduate Students

We welcome the master course and doctor course students